The long range objective of this research program is to develop highly stereoselective syntheses of biologically active natural products by routes involving intramolecular Diels-Alder (IMDA) reactions. A second goal is the development of synthetic methodology that will be used by synthetic organic and medicinal chemists for the stereoselective synthesis of biologically active molecules. Specific aims for the next grant period are: (1) Completion of Total Syntheses of Kijanolide and Tetronolide. Tetronolide is the aglycone of an antibiotic with significant antitumor activity, while kijanolide is the aglycone of an antibiotic with activity against an unusual range of microorganisms including Propionibacterium and Plasmodium species. A highly stereoselective synthesis of the enantiomerically pure bottom half of these natural products was developed in the preceding grant period, and chiral ketene equivalent 26 has been shown to undergo highly stereoselective exo Diels-Alder reactions, thus paving the way for efficient, enantioselective syntheses of the top halves. The syntheses of the top half fragments will be completed in the coming grant period, then they will be coupled with the bottom half to complete the total syntheses. (2) Completion of a Total Synthesis of Nargenicin A1. Nargenicin A1 is an antibiotic with significant antibacterial activity against Staphylococcus aureus and other gram-positive bacteria. Our original approach has been compromised by the unanticipated competition of boat-like transition states in decatrienone IMDA reactions. The synthesis has thus been redesigned to proceed via the transannular IMDA reaction of 18-membered macro-cyclic tetraene 74. It is anticipated that the macrocycle will serve as a stereochemical control vehicle for the IMDA reaction, thereby solving the stereochemical problems encountered in the original IMDA approach. The trans-annular cycloaddition strategy has additional strategic advantages that may lead to highly efficient solution to this synthesis (e.g., the greater ease of 18-membered ring formation, compared to the 10-membered lactone that must be closed in alternative approaches) (3) Stereochemical Studies of Transannular Intramolecular Diels-Alder Reactions. Basic stereochemical studies of the transannular cyclizations of simple (E,E,E)-cyclododeca-1,6,8-trienes, cyclotrideca-1,6,8-trienes and cyclotetradeca-1,7,9-trienes will be performed to define the limits of stereoselectivity. New methodology for the synthesis of macrocyclic trienes will be explored and developed, specifically the Pd (o) catalyzed macrocyclic cross couplings of vinylhalides with vinylstannanes and/or vinylboronic acids, intramolecular Nozaki reactions and the McMurry reductive cyclizations of dicarbonyl compounds. The potential for applications of the transannular cycloaddition technology in the synthesis of biologically active natural products is great. Two possible synthetic targets are ikarugamycin and forskolin, but the initiation of syntheses of such targets will await the results of the initial methodological and stereochemical investigations.